(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau
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1 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/ Al 02 November 2017 ( ) W!P O PCT (51) International Patent Classification: TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, C07D 215/48 ( ) A61P 35/00 ( ) EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, A61K 31/47 ( ) MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (21) International Application Number: KM, ML, MR, NE, SN, TD, TG). PCT/CZ20 17/ (22) International Filing Date: Declarations under Rule 4.17: 27 April 2017 ( ) as to applicant's entitlement to apply for and be granted a (25) Filing Language: English patent (Rule 4.1 7(H)) (26) Publication Language: English Published: with international search report (Art. 21(3)) (30) Priority Data: PV April 2016 ( ) CZ (71) Applicant: ZENT A, K.S. [CZ/CZ]; U Kabelovny 130, CZ Praha 10 (CZ). (72) Inventors: ZVATORA, Pavel; Ciglerova 1090/32, CZ Praha (CZ). DAMMER, Ondrej; Novotneho 975, CZ Hostivice (CZ). KREJCIK, Lukas; Moravanska 474, CZ Praha 9 (CZ). LEHNERT, Petr; Ellnerove 3104/4, CZ Praha 10 (CZ). (74) Agent: JIROTKOVA, Ivana et al; Rott, Ruzicka & Guttmann, Vinohradska 37, CZ Praha 2 (CZ). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (54) Title: SALTS OF LENVATINIB (I) (57) Abstract: The present invention relates to solid forms of 4- [3-chloro-4- (cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide (CAS No ) of formula I, known as lenvatinib, with an acid that is selected from the group consisting of phosphoric acid, tartaric acid, citric acid, camphorsulfonic acid, isethionic acid and naphthalenedisulfonic acid. Other ob jects are preparation methods of a salt of lenvatinib with the above mentioned acids and its use in a drug form. The drug with the name Lenvima, which contains lenvatinib mesylate, has been approved by the Food and Drug Administration (FDA) for the treatment of locally recurrent or metastatic, progressive thyroid cancer, resistant to radioactive iodine.
2 Salts of lenvatinib Field of the Invention The invention relates to solid forms of 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]- 7-methoxy-quinoline-6-carboxamide (CAS No ) of formula I, known as lenvatinib, methods of their preparation and use in a drug form. (I) The drug with the name Lenvima, which contains lenvatinib mesylate, has been approved by the Food and Drug Administration (FDA) for the treatment of locally recurrent or metastatic, progressive thyroid cancer, resistant to radioactive iodine. Background Art Preparation of lenvatinib and its isolation was first described in the patent application WO , in Example 368. The patent application WO 2004/ described preparation and characterization methods of two crystalline forms of lenvatinib free base (form A, B). The patent application WO 2005/ described preparation and characterization methods of crystalline salts of lenvatinib, in particular lenvatinib hydrochloride, hydrobromide, p- toluenesulfonate, sulphate, esylate, three polymorphic forms of lenvatinib mesylate (form A, B and C) and several mesylate and esylate solvates. The patent application WO 2006/ describes preparation and characterization methods of amorphous forms of lenvatinib esylate and lenvatinib mesylate. The patent application WO 2014/ describes preparation and characterization methods of an amorphous form of lenvatinib free base. Pharmaceutical compositions containing lenvatinib or its salts are disclosed in the patent applications WO 2006/ and WO 201 1/
3 Many pharmaceutical solid compounds can form salts or cocrystals with suitable counterions and thus exist in various crystalline forms that have different crystal units and thus different physicochemical properties as the melting point, solubility, dissolution rate as well as biological availability. To distinguish individual solid phases of a compound, several solidstate analytic methods can be used, e.g. X-ray powder diffraction, solid-state NMR, Raman spectroscopy as well as thermoanalytic methods. Discovering new solid phases (salts and cocrystals) of an active pharmaceutical ingredient offers an opportunity to select a suitable modification with desired physicochemical properties and processability and improve the characteristics of the chemical product. For this reason, there is an obvious need of novel solid forms (salts and cocrystals) of lenvatinib. Disclosure of the Invention The object of the invention are pharmaceutically acceptable salts of lenvatinib and methods of their preparation. These solid forms of lenvatinib are prepared through a reaction of lenvatinib free base with suitable inorganic or organic acids in a suitable solvent or mixtures of solvents. The prepared solid forms have suitable physicochemical characteristics for use in the pharmaceutical industry and formulation of new drug forms. An object of this invention is the salt of lenvatinib with phosphoric acid, tartaric acid, citric acid, camphorsulfonic acid, isethionic acid and naphthalenedisulfonic acid. Another object of the invention is the salt of lenvatinib with phosphoric acid, exhibiting the characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 8.1; 11.3; 20.3; 21.5 and 25.8 ± 0,2 2-theta. In some embodiments, the salt of lenvatinib with phosphoric acid is further characterized by the differential scanning calorimetry curve with the melting point at 178 C. Another object of the invention is a preparation method of the salt of lenvatinib with phosphoric acid wherein the free base of lenvatinib is dissolved in a suitable solvent and phosphoric acid is added subsequently. A suitable solvent is a solvent selected from the group consisting of aliphatic C1-C4 alcohols, ketones, esters, nitriles, water or their mixtures, preferably from acetone, ethyl acetate, acetonitrile, methanol, ethanol, water or their mixtures. Another object of the invention is the salt of lenvatinib with tartaric acid, exhibiting the characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 4.0; 11.1; 15.2; 20.2 and 22.4 ± theta. In some embodiments, the salt of lenvatinib with
4 tartaric acid is further characterized by the differential scanning calorimetry curve with the melting point at 169 C. Another object of the invention is the salt of lenvatinib with citric acid, exhibiting the characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 8.0; 12.0; 13.9; 20.0 and 24.3 ± theta. In some embodiments, the salt of lenvatinib with citric acid is further characterized by the differential scanning calorimetry curve with the melting point at 148 C. Another object of the invention is the salt of lenvatinib with camphorsulfonic acid, exhibiting the characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 4.6; 12.8; 14.4; 16.4; 18.1; 18.5; 20.1 and 25.8 ± theta. In some embodiments, the salt of lenvatinib with camphorsulfonic acid is further characterized by the differential scanning calorimetry curve with the melting point at 2 1 C. Another object of the invention is the salt of lenvatinib with isethionic acid, exhibiting the characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 5.1; 9.4; 14.6; 17.3; 20.1 and 25.4 ± theta. In some embodiments, the salt of lenvatinib with isethionic acid is further characterized by the differential scanning calorimetry curve with the melting point at 144 C. Another object of the invention is the salt of lenvatinib with naphthalenedisulfonic acid, exhibiting the characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 5.8; 10.2; 13.5; 15.6; 19.9 and 23.3 ± theta. In some embodiments, the salt of lenvatinib with naphthalenedisulfonic acid is further characterized by the differential scanning calorimetry curve with the melting point at 155 C. Another object of the invention is a preparation method of a salt of lenvatinib with an acid in accordance with the present invention wherein the free base of lenvatinib is dissolved in a suitable solvent together with an acid that is selected from the group consisting of tartaric acid, citric acid, camphorsulfonic acid, isethionic acid and naphthalenedisulfonic acid. A suitable solvent is a solvent selected from the group consisting of aliphatic C1-C4 alcohols, ketones, esters, nitriles, water or their mixtures, preferably from acetone, ethyl acetate, acetonitrile, methanol, ethanol, water or their mixtures. Another object of the invention is the use of a solid form of a salt of lenvatinib with an acid in accordance with the present invention for the preparation of a pharmaceutical composition.
5 Another object of the invention is a pharmaceutical composition comprising a solid form of a salt of lenvatinib with an acid in accordance with the present invention and at least one pharmaceutically acceptable excipient. Brief description of the Drawings Figure 1: X-ray powder pattern of lenvatinib phosphate Figure 2: X-ray powder pattern of lenvatinib tartrate Figure 3: X-ray powder pattern of lenvatinib citrate Figure 4: X-ray powder pattern of lenvatinib camphorsulfonate Figure 5: X-ray powder pattern of lenvatinib isethionate Figure 6: X-ray powder pattern of lenvatinib naphthalenedisulfonate Detailed description of the Invention Although preparation of a salt by a reaction of an acid and base is a well-known method, it is always a problem to obtain the required salts in the solid phase and purity corresponding to the demands for their pharmaceutical use. Biological availability greatly depends on whether a crystalline or amorphous product is obtained. An amorphous product is usually more readily soluble, it cannot often be obtained in the required quality and it is also often unstable. Conversely, compared to the amorphous form, a crystalline product is often stable, its required purity is easier to achieve and it dissolves more slowly. The problem may be solved by crystalline forms of active pharmaceutical ingredients with a lower melting point when such crystal arrangement guarantees higher solubility of the crystalline form, or by the use of the amorphous form of the active pharmaceutical ingredient. This invention provides several crystalline salts of lenvatinib, the obtained crystalline forms exhibiting a lower melting point than the crystalline lenvatinib mesylate used in the drug Lenvima. The invention prefers crystalline forms of salts of lenvatinib with counterfoils of acids whose salts are physiologically common, or they represent intermediates of metabolites in biochemical processes. These compounds comprise phosphoric acid, citric acid and tartaric acid.
6 An object of this invention are solid forms of lenvatinib with phosphoric acid, tartaric acid, naphthalenedisulfonic acid, citric acid, camphorsulfonic acid and isethionic acid in various molar ratios. Within the invention, 1:1 molar ratios are preferred. Solid forms of lenvatinib with these acids can be prepared in adequate ratios and yields with high chemical purity in a crystalline or amorphous form. These solid forms can be both anhydrous and/or non-solvated, and they can have the form of hydrates/solvates of the respective solvents. The prepared solid forms of lenvatinib may have various internal arrangements (polymorphism) with different physicochemical properties depending on the conditions of their preparation. For this reason, the invention relates to individual crystals or their mixtures in any ratio. These solid forms are suitable for the preparation of lenvatinib with a high chemical purity. The preparation of the solid forms of lenvatinib in accordance with the present invention is carried out through a reaction of levantinib base with phosphoric acid, tartaric acid, naphthalenedisulfonic acid, citric acid, camphorsulfonic acid and isethionic acid. The reaction is conducted in a suitable solvent, which can be ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water or their mixtures. Aliphatic C1-C4 alcohols, ketones, esters, nitriles or their mixtures are preferred. The most commonly used solvents are acetone, ethyl acetate, acetonitrile, methanol, ethanol, water or their mixtures. The final product is typically precipitated or crystallized at temperatures in the range of - 30 C to the boiling point of the solvent. Lenvatinib free base (form B) was prepared in accordance with the process disclosed in the patent application WO 2004/ Differential scanning calorimetry (DSC) was applied to measure the melting point of crystalline form B of lenvatinib free base of 204 C. Crystalline salt of lenvatinib with methanesulfonic acid (form C) was prepared according to the process disclosed in the patent application WO 2005/ Differential scanning calorimetry (DSC) was applied to measure the melting point of the crystalline salt of lenvatinib with methanesulfonic acid (form C) of 238 C. The crystalline form of lenvatinib phosphate (prepared according to Example 1) is Characterized by the reflections presented in Table 1. Table 1 includes reflections whose relative intensity value is higher than 1%. Characteristic diffraction peaks of the crystalline form of lenvatinib phosphate in accordance with the present invention with the use of CuKa
7 radiation are: 8.1; 11.3; 20.3; 21.5 and 25.8 ± 0,2 2-theta. The X-ray powder pattern is shown in Fig. 1. Table 1 Interplanar spacing [A] Position [ 2Th.] [A]=0.1nm Rel. intensity [%] ;
8 Differential scanning calorimetry (DSC) was applied to measure the melting point of the crystalline form of lenvatinib phosphate of 178 C. The crystalline form of lenvatinib tartrate (prepared according to Example 2) is characterized by the reflections presented in Table 2. Table 2 includes reflections whose relative intensity value is higher than 1%. Characteristic diffraction peaks of the crystalline form of lenvatinib tartrate in accordance with the present invention with the use of CuK radiation are: 4.0; 11.1; 15.2; 20.2 and 22.4 ± theta. The X-ray powder pattern is shown in Fig. 2. Table 2 Interplanar spacing [A] Position [ 2Th.] [A]=0.1nm Rel. intensity [%]
9 Differential scanning calorimetry (DSC) was applied to measure the melting point of the crystalline form of lenvatinib tartrate of 169 C. The crystalline form of lenvatinib tartrate (prepared according to Example 3) is characterized by the reflections presented in Table 3. Table 3 includes reflections whose relative intensity value is higher than 1%. Characteristic diffraction peaks of the crystalline form of lenvatinib citrate in accordance with the present invention with the use of CuKa radiation are: 8.0; 12.0; 13.9; 20.0 and 24.3 ± theta. The X-ray powder pattern is shown in Fig. 3. Table 3 Interplanar spacing [A] Position [ 2Th.] [A]=0.1nm Rel. intensity [%]
10 Differential scanning calorimetry (DSC) was applied to measure the melting point of the crystalline form of lenvatinib citrate of 148 C. The crystalline form of lenvatinib camphorsulfonate (prepared according to Example 4) is characterized by the reflections presented in Table 4. Table 4 includes reflections whose relative intensity value is higher than 1%. Characteristic diffraction peaks of the crystalline form of lenvatinib camphorsulfonate in accordance with the present invention with the use of CuKa radiation are: 4.6; 12.8; 14.4; 16.4; 18.1; 18.5; 20.1 and 25.8 ± theta. The X-ray powder pattern is shown in Fig. 4. Table 4 Position [ 2Th.] Interplanar spacing [A] Rel. intensity [%] [A]=0.1nm
11 Position [ 2Th.] Interplanar spacing [A] Rel. intensity [%] [A]=0.1nm Differential scanning calorimetry (DSC) was applied to measure the melting point of the crystalline form of lenvatinib camphorsulfonate of 2 1 C. The crystalline form of lenvatinib isethionate (prepared according to Example 5) is characterized by the reflections presented in Table 5. Table 5 includes reflections whose relative intensity value is higher than 1%. Characteristic diffraction peaks of the crystalline form of lenvatinib isethionate in accordance with the present invention with the use of CuKa radiation are: 5.1; 9.4; 14.6; 17.3; 20.1 and 25.4 ± theta. The X-ray powder pattern is shown in Fig. 5.
12 Table 5 Differential scanning calorimetry (DSC) was applied to measure the melting point of the crystalline form of lenvatinib isethionate of 144 C. The crystalline form of lenvatinib naphthalenedisulfonate (prepared according to Example 6) is characterized by the reflections presented in Table 6. Table 6 includes reflections whose relative intensity value is higher than 1%. Characteristic diffraction peaks of the crystalline form of lenvatinib naphthalenedisulfonate in accordance with the present invention with the use of CuKa radiation are: 5.8; 10.2; 13.5; 15.6; 19.9 and 23.3 ± theta. The X-ray powder pattern is shown in Fig. 6.
13 Table 6 Position Interplanar spacing [A] [ 2Th.] [A]=0.1nm Rel. intensity [%]
14 Differential scanning calorimetry (DSC) was applied to measure the melting point of the crystalline form of lenvatinib naphthalenedisulfonate of 155 C. The invention is clarified in a more detailed way using the embodiment examples below. These examples, which illustrate the preparation of solid forms of lenvatinib only have an illustrative character and do not restrict the scope of the invention in any respect. The solid forms of the salts of lenvatinib prepared in accordance with the present invention can be used for the preparation of pharmaceutical compositions, especially solid drug forms, e.g. tablets or capsules. Such pharmaceutical compositions can contain at least one excipient from the group of fillers (e.g. lactose), binders (e.g. microcrystalline cellulose), disintegrants (e.g. sodium salt of croscarmellose), lubricants (e.g. magnesium stearate), surfactants etc. A salt of lenvatinib can be mixed with the above mentioned excipients, screened through a sieve and the resulting mixture can be tabletted or filled into capsules. The tablets can be further coated with common coating compounds, e.g. polyvinyl alcohol or polyethylene glycol. Experimental part X-ray powder diffraction The diffractograms were obtained using an X'PERT PRO MPD PANalytical powder diffractometer, used radiation CuKa (λ nm (1.542 A)), excitation voltage: 45 kv, anode current: 40 A, measured range: Θ, increment: Θat the dwell time at a reflection of 0.5 s, the measurement was carried out with a flat sample with the area/thickness of 10/0.5 mm. For the correction of the primary array 0.02 rad Soller slits, a 10mm mask and a 1/4 fixed anti-dispersion slit were used. The irradiated area of the sample is 10 mm, programmable divergence slits were used. For the correction of the secondary array 0.02 rad Soiler slits and a 5.0 anti-dispersion slit were used. Differential Scanning Calorimetry (DSC) The records of the solid crystalline lenvatinib salts were measured with the use of a DSC Pyris 1 device by Perkin Elmer. The sample charge in a standard Al pot was between mg and the heating rate was 10 C7min. The temperature program that was used consists of 1 min of stabilization at the temperature of 0 C and then of heating up to 300 C at the heating rate bf l C/min. As the carrier gas 4.0 N 2 was used at the flow of 20 ml/min.
15 Ultra high-performance liquid chromatography (UHPLC) Impurities were separated from the prepared salts of lenvatinib on an Ascentis Express CI 8 column, 2.7 um, 4.6 x 100 mm with the use of the mobile phase gradient: mobile phase: A: phosphate buffer (1.32 g) (NH4)2HP04 s dissolved in 1 1of MQ water, ph of the solution is adjusted to the value of 7.5 ± 0.05 with the use of 50% phosphoric acid. B: acetonitrile sample solvent: 100% MeOH detection: spectrophotometric 251 r n injected quantity: 0.5 µΐ autosampler temperature: 18 C column temperature: 35 C analysis time: 12 min sample preparation: The amount of 10.0 mg of the tested substance is dissolved in 100% methanol. It is put in an ultrasonic bath for 5 min and after cooling to the laboratory temperature it is diluted with the same solvent to 10.0 ml. Examples The crystalline free base of lenvatinib (form B) was prepared in accordance with the process disclosed in the patent application WO 2004/ Example 1 Preparation of crystalline lenvatinib phosphate Crystalline free base of 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide (form B) in the quantity of 203 mg ( mol) was dissolved in
16 3.86 ml of methanol in a hot state. After cooling down to the room temperature, the amount of µΐ ( mol) of phosphoric acid (85%) was added to this solution under continuous stirring. The mixture was stirred for 12 h at the laboratory temperature. Then, the solvent was left to evaporate in a vacuum drier at the room temperature. UHPLC purity 99.9%. X-ray powder pattern in Fig. 1. Melting point in accordance with DSC 178 C. Example 2 Preparation of crystalline lenvatinib tartrate Crystalline free base of 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide (form B) in the quantity of 198 mg ( mol) together with mg ( mol) of I-(+)-tartaric acid was dissolved in 3.76 ml of methanol in a hot state. The solution was cooled down to the room temperature under continuous stirring and the mixture was stirred at the laboratory temperature for 12 h. Then, the solvent was left to evaporate in a vacuum drier at the room temperature. UHPLC purity 99.9%. X-ray powder pattern in Fig. 2. Melting point in accordance with DSC 169 C. Example 3 Preparation of crystalline lenvatinib citrate Crystalline free base of 4-[3-cMoro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide (form B) in the quantity of 210 mg ( mol) together with mg ( mol) of citric acid was dissolved in 20 ml of ethyl acetate in a hot state. The solution was cooled down to the room temperature under continuous stirring and the mixture was stirred at the laboratory temperature for 12 h. Then, the solvent was left to evaporate in a vacuum drier at the room temperature. UHPLC purity 99.9%. X-ray powder pattern in Fig. 3. Melting point in accordance with DSC 148 C. Example 4 Preparation of crystalline lenvatinib camphorsulfonate Crystalline free base of 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide (form B) in the quantity of 250 mg ( ^ mol) together with mg ( mol) of camphorsulfonic acid (98%) was dissolved in 4.75 ml of methanol in a hot state. The solution was cooled down to the room temperature under continuous stirring and the mixture was stirred at the laboratory temperature for 12 h. Then,
17 the solvent was left to evaporate in a vacuum drier at the room temperature. UHPLC purity 99.9%. X-ray powder pattern in Fig. 4. Melting point in accordance with DSC 2 11 C. Example Preparation of crystalline lenvatinib isethionate Crystalline free base of 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide (form B) in the quantity of 220 mg ( mol) together with mg ( mol) of isethionic acid was dissolved in 4.18 ml of methanol in a hot state. The solution was cooled down to the room temperature under continuous stirring and the mixture was stirred at the laboratory temperature for 12 h. Then, the solvent was left to evaporate in a vacuum drier at the room temperature. UHPLC purity 99.4%. X-ray powder pattern in Fig. 5. Melting point in accordance with DSC 144 C. Example 6 Preparation of crystalline lenvatinib naphthalenedisulfonate Crystalline free base of 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide (form B) in the quantity of 247 mg ( mol) together with 215 mg ( mol) of 1,5-naphthalenedisulfonic acid tetrahydrate (97%) was dissolved in 8 ml of methanol in a hot state. The solution was cooled down to the room temperature under continuous stirring and the mixture was stirred at the laboratory temperature for 12 h. Then, the solvent was left to evaporate in a vacuum drier at the room temperature. UHPLC purity 76%. X-ray powder pattern in Fig. 6. Melting point in accordance with DSC 155 C.
18 CLAIMS 1. A salt of lenvatinib with an acid in a solid form, wherein the acid is selected from the group consisting of phosphoric acid, tartaric acid, citric acid, camphorsulfonic acid, isethionic acid and naphthalenedisulfonic acid. 2. The salt with an acid in accordance with claim 1, wherein the acid is phosphoric acid, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 8.1; 11.3; 20.3; 21.5 and 25.8 ± theta. 3. The salt of lenvatinib with the acid in accordance with claim 2, characterized by the differential scanning calorimetry curve with the melting point at 178 C. 4. A method for preparing the salt of lenvatinib with an acid as defined in claims 1 to 3, characterized in that the free base of lenvatinib is dissolved in a suitable solvent arid phosphoric acid is added subsequently. 5. The method of preparing in accordance with claim 4, characterized in that the suitable solvent is a solvent selected from the group consisting of aliphatic C 1 -C4 alcohols, ketones, esters, nitriles, water or their mixtures, preferably from acetone, ethyl acetate, acetonitrile, methanol, ethanol, water or their mixtures. 6. The salt of lenvatinib with an acid in accordance with claim 1, wherein the acid is tartaric acid, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 4.0; 11.1; 15.2; 20.2 and 22.4 ± 0.2* 2-theta. 7. The salt of lenvatinib with the acid in accordance with claim 6, characterized by the differential scanning calorimetry curve with the melting point at 169 C. 8. The salt of lenvatinib with an acid in accordance with claim 1, wherein the acid is citric acid, exhibiting the following characteristic reflections in me X-ray powder 1 pattern with the use of CuKa radiation: 8.0; 12.0; 13.9; 20.0 and 24.3 ± theta.
19 9. The salt of lenvatinib in accordance with claim 8, characterized by the differential scanning calorimetry curve with the melting point at 148 C. 10. The salt of lenvatinib with an acid in accordance with claim 1, wherein the acid is camphorsulfonic acid, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuK radiation: 4.6; 12.8; 14.4; 16.4; 18.1; 18.5; 20.1 and 25.8 ± theta. 11. The salt of lenvatinib with the acid in accordance with claim 10, characterized by the differential scanning calorimetry curve with the melting point at 2 11 C. 12. The salt of lenvatinib with an acid in accordance with claim 1, wherein the acid is isethionic acid, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 5.1; 9.4; 14.6; 17.3; 20.1 and 25.4 ± h e a 13. The salt of lenvatinib with the acid in accordance with claim 1, characterized by the differential scanning calorimetry curve with the melting point at 144 C. 14. The salt of lenvatinib with an acid in accordance with claim 1, wherein the acid is naphthalenedisulfonic acid, exhibiting the following characteristic reflections in the X- ray powder pattern with the use of CuKa radiation: 5.8; 10.2; 13.5; 15.6; 19.9 and 23.3 ± theta. 15. The salt of lenvatinib with the acid in accordance with claim 14, characterized by the differential scanning calorimetry curve with the melting point at 155 C. 16. A method for preparing the salt of lenvatinib with an acid as defined in claims 1 and 6 to 15, characterized in that the free base of lenvatinib is dissolved in a suitable solvent together with the acid that is selected from the group consisting of tartaric acid, citric acid, camphorsulfonic acid, isethionic acid and naphthalenedisulfonic acid.
20 17. The method of preparing in accordance with claim 16, characterized in that the suitable solvent is a solvent selected from the group consisting of aliphatic C C 4 alcohols, ketones, esters, nitriles, water or their mixtures, preferably from acetone, ethyl acetate, acetonitrile, methanol, ethanol, water or their mixtures. 18. Use of the solid form of a salt of lenvatinib with an acid as defined in claims 1 to 3 and 6 to 15 for the preparation of a pharmaceutical composition. 19. A pharmaceutical composition, characterized in that it contains a solid form of a salt of lenvatinib with an acid as defined in claims 1 to 3 and 6 to 15 and at least one pharmaceutically acceptable excipient.
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27 A. CLASSIFICATION O F SUBJECT MATTER INV. C07D215/48 A61K31/47 A61P35/00 ADD. According to International Patent Classification (IPC) o r to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) C07D Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) EPO-Internal, CHEM ABS Data, WPI Data C. DOCUMENTS CONSIDERED TO B E RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. EP Al (EISAI CO LTD [ P] ) September 2006 ( ) ci ted i n the appl i cati on paragraphs [0009], [0010] ; cl aims EP Al (EISAI R&D MAN CO LTD 1-19 [ P] ) 5 March 2008 ( ) paragraphs [0009], [0010] ; cl aims US 2007/ Al (ARIM0T0 ITARU [JP] ET 1-19 AL) 24 May 2007 ( ) cl aims -/- X Further documents are listed in the continuation of Box C. See patent family annex. * Special categories of cited documents : "A" document defining the general state of the art which is not considered to be of particular relevance "T" later document published after the international filing date or priority date and not in conflict with the application but cited to understand the principle o r theory underlying the invention "E" earlier application or patent but published o n or after the international "X" document of particular relevance; the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive "L" documentwhich may throw doubts on priority claim(s) orwhich is step when the document is taken alone cited to establish the publication date of another citation or other "Y" document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve an inventive step when the document is "O" document referring to an oral disclosure, use, exhibition or other combined with one o r more other such documents, such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 13 July /07/2017 Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B Patentlaan 2 NL HV Rijswijk Tel. (+31-70) , Beyss-Kahana, El l en Fax: (+31-70)
28 C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. CAI RA: "Crystal l i ne Polymorphi sm of Organi c Compounds", TOPICS I N CURRENT CHEMIS, SPRINGER, BERLIN, DE, vol. 198, 1 January 1998 ( ), pages , XP , ISSN : chapter 3. 1paragraph bri dgi ng pages ;
29 Patent document Publication Patent family Publication cited in search report date member(s) date EP Al AU Al B R PI A CA Al CN A CN A CN A CN A CY Tl DK T EP Al EP A ES T HK Al HK Al HR P Tl HU E T I L A P B P A P W Al KR A KR A KR A MX PA A MY A NO Bl NZ A PT E RU C SI Tl T B US Al O Al ZA B EP Al AU Al CA Al CN A EP Al I L A J P B J P W Al KR A W Al US Al US Al W Al
(43) International Publication Date Χ t it 1 6 October 2011 ( ) WO 2U11/ A l
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